Researchers at UC San Diego have made a groundbreaking discovery that challenges previous assumptions about liver cancer. They have identified a protein, previously associated with the disease, as a key factor in protecting against its development.
Liver cancer ranks as the sixth most prevalent form of cancer worldwide and is responsible for a significant number of cancer-related deaths. Its occurrence is influenced by various environmental factors and metabolic stressors such as obesity, viral hepatitis, and steatohepatitis—a condition characterized by inflammation and fatty deposits in the liver.
These stressors cause detrimental effects by inducing the death of hepatocytes, the primary cells in the liver. Subsequently, this cell death triggers an inflammatory response, which prompts the liver to regenerate hepatocytes. However, this rapid cell proliferation also increases the likelihood of tumor growth.
In a recent study, scientists at UC San Diego School of Medicine delved into the role of activating transcription factor 4 (ATF4), a crucial mediator of the liver’s stress response. Contrary to previous beliefs associating ATF4 with advanced liver cancer, the researchers discovered that it actually safeguards the liver against hepatocyte death and subsequent tumor formation. This unexpected finding has the potential to inspire novel clinical approaches for preventing liver disease and cancer.
The study, published in the Journal of Hepatology, was led by senior authors Michael Karin, Ph.D., Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine, and Benjamin C. Yaden, Ph.D., Associate Vice President of Diabetes Novel Therapies and External Innovation at Eli Lilly.
Normally, ATF4 levels remain low in healthy cells but increase when cells experience stress. To examine its role in liver cancer progression, the researchers developed a mouse model with hepatocytes lacking ATF4. The mice were then exposed to various stressors to induce liver damage and tumor formation.
Surprisingly, the ATF4-deficient mice exhibited increased hepatocyte death, inflammation, compensatory cellular proliferation, and accelerated liver cancer development. These results strongly indicated that ATF4 played a protective role against liver cancer.
Additional experiments conducted by postdoctoral fellow Feng He, Ph.D., further confirmed that ATF4 stimulated the expression of SLC7A11, a protein essential for maintaining hepatocyte homeostasis. SLC7A11, in turn, helped suppress a specific type of cell death called ferroptosis. By reducing the occurrence of ferroptosis, the ATF4-SLC7A11 axis shielded hepatocytes and slowed the progression from liver damage to liver cancer.
Karin stated, “Our study suggests that ferroptosis may be the most relevant form of hepatocyte death that leads to inflammation, compensatory proliferation, and cancer in the liver.” The researchers believe that the use of ferroptosis inhibitors or ATF4 activators could have clinical benefits in preventing steatohepatitis and its progression to cancer.
The study received funding from the Superfund Basic Research Program, the National Institutes of Health, a C3 Pedal the Cause grant, the National Natural Science Foundation of China, and the Eli Lilly LIFA program.
Co-authors of the study include Peng Zhang and Junlai Liu from UC San Diego, Ruolei Wang from Shanghai University of Traditional Chinese Medicine, and Randal J. Kaufman from Sanford Burnham Prebys Medical Discovery Institute.
Notably, Benjamin C. Yaden is a full-time employee of Eli Lilly and Company, while Feng He received partial support from the Eli Lilly LIFA program.
Table of Contents
Frequently Asked Questions (FAQs) about Liver cancer prevention
What did the researchers discover about the protein ATF4 and liver cancer?
The researchers discovered that the protein ATF4, previously associated with liver cancer, actually plays a protective role in preventing hepatocyte death and subsequent tumor formation in the liver. This unexpected finding could inspire new strategies for preventing liver disease and cancer.
What is the significance of this discovery for liver cancer prevention?
This discovery is significant because it identifies ATF4 as a potential key factor in preventing liver cancer. By blocking a specific type of cell death called ferroptosis, ATF4 helps protect hepatocytes and slows down the progression from liver damage to liver cancer. This could lead to the development of new clinical approaches for preventing liver disease and cancer.
How was the study conducted?
The study involved using a mouse model with hepatocytes lacking ATF4. The mice were exposed to various stressors to induce liver damage and tumor formation. The researchers then observed the effects of ATF4 deficiency on hepatocyte death, inflammation, cellular proliferation, and liver cancer development. Additional experiments were conducted to confirm the role of ATF4 in promoting the expression of SLC7A11, a protein that helps maintain hepatocyte homeostasis.
What are the potential clinical implications of this research?
The researchers believe that targeting ferroptosis or activating ATF4 could be clinically useful in preventing steatohepatitis and its progression to liver cancer. Inhibitors of ferroptosis or activators of ATF4 could potentially be developed as therapeutic interventions to protect against liver disease and reduce the risk of liver cancer.
Who funded this study?
The study received funding from various sources, including the Superfund Basic Research Program, the National Institutes of Health, a C3 Pedal the Cause grant, the National Natural Science Foundation of China, and the Eli Lilly LIFA program.
More about Liver cancer prevention
- Journal of Hepatology
- UC San Diego School of Medicine
- Eli Lilly
- National Institutes of Health (NIH)
- Superfund Basic Research Program
- C3 Pedal the Cause
- National Natural Science Foundation of China
- Sanford Burnham Prebys Medical Discovery Institute
